Method and device for measuring the quantity of an active principle contained in a reservoir

ABSTRACT

A solution of active principle, in ionized form, impregnates a layer (2) forming part of the reservoir (1). A measurement of the quantity of active principle contained in this layer is derived from a measurement of the conductivity of this layer. The measurement device comprises a) first (7) and second (10) electrodes placed on either side of and in electrical contact with at least a part of the layer (2) of the impregnated material of the reservoir, b) means (5) for passing the electric current of predetermined strength through the impregnated material and c) means (6) sensitive to the voltage (V) picked up between the electrodes (7, 10) in order to calculate the quantity of active principle contained in the reservoir.

The present invention relates to a method and to a device for measuringthe quantity of an active principle contained in a reservoir, as well asto a reservoir designed to allow such a measurement. More particularly,the invention relates to such a method, device and reservoir employed inthe context of transdermal delivery of medicinal products assisted byiontophoresis.

FIG. 2 of the attached drawing diagrammatically represents means whichcan be used for carrying out such delivery. These means essentiallycomprise, in a known manner, a reservoir 1 comprising a layer 2 of amaterial, such as a hydratable polymer or "hydrogel", impregnated with asolution of the active principle, this layer 2 being designed to beplaced in contact with the skin 3 of a patient. The active principle ispresent in the solution in an ionized form, so that its passage throughthe skin of the patient can be assisted by iontophoresis. In order to dothis, the reservoir is connected to an electronic module 4 comprisingmeans 5 for generating and means 6 for controlling a so-called"therapeutic" current which passes through the patient between anelectrode 7, which may form part of the reservoir 1, and an adjacentelectrode 8, so as to establish current lines 9 under the skin of thepatient. The ions of the active principle flow down these current lines,starting from the reservoir 1 then crossing the dermis and passing intothe underlying capillary vessels. The control means 6, for example amicrocontroller, control the amplitude and the waveform of the appliedcurrent so that the quantity of active principle passing into the bloodis modulated in time according to a precise delivery program,established on the basis of pharmacological considerations.

This program should thus respect the minimum and maximum values of thedoses of active principle applied per unit time. An overdose may behighly dangerous for the safety of the patient, whereas an insufficientdose does not allow the desired pharmacological activity to be ensured.It should be pointed out, in this regard, that the quantities of activeprinciple to be delivered do, of course, vary from one active principleto another, and that the delivery program should be capable of adaptingto the variations in the permeability of the skin, from one patient toanother.

It will be understood that, in order to ensure that the program isfollowed, it is then necessary for the control means to be fed back witha measurement of the quantity of active principle actually delivered tothe patient, all along the delivery time of said active principle.

For this purpose, a method and an apparatus for dosage of the quantitiesof active principle delivered, operating by integration over time of the"therapeutic" current passing through the patient between the electrode7 and the electrode 8 are proposed in European Patent Application No.0,277,314 in the name of R. TAPPER. This method is burdened with thedrawback that the current passing between the two electrodes is notnecessarily representative of the number of ions of the active principlewhich have left the reservoir and passed into the blood of the patient.Iontophoresis does in fact have an efficiency which is less than one,and in addition, can vary from one patient to another, and from onecondition of the skin of the patient to another, this condition varyingprogressively during the delivery of the medicinal product, which maycommonly last several hours.

Another solution which is theoretically envisageable, but difficult,might consist in in vivo dosage of the quantity of active principlepresent in the blood of the patient.

The object of the present invention is to provide a method and a devicefor measuring the quantity of an active principle contained in areservoir, which does not have the abovementioned drawbacks of the priorart.

A further object of the invention is to provide an active principlereservoir which is suitable for implementing the method according to theinvention.

The objects of the invention, as well as others which will emerge onreading the following description, are achieved with a method formeasuring the quantity of an active principle contained in an ionizedform in a reservoir consisting of a layer of a material impregnated witha solution of this active principle, which is noteworthy in that theconductivity of the impregnated material is measured and a measurementof the quantity of active principle contained in the reservoir isderived from this conductivity measurement. As will be seen hereinbelow,the conductivity or the conductance of the reservoir is a function ofthe quantity of active principle contained in this reservoir. Bysubtraction, the quantity of active principle which has passed into theblood of a patient during transdermal delivery of medicinal products canbe deduced therefrom.

According to a characteristic of the method according to the invention,in order to measure the conductivity of the impregnated material, acurrent of predetermined strength is passed through the latter, and theelectric voltage which then appears between two electrodes separated byat least a part of the layer of the impregnated material is measured.

In order to implement this method, the invention provides a devicecomprising a) first and second electrodes placed on either side of andin electrical contact with at least a part of the layer of theimpregnated material of the reservoir, b) means for passing the electriccurrent of predetermined strength through the impregnated material andc) means sensitive to the voltage picked up between the electrodes inorder to calculate the quantity of active principle contained in thereservoir.

The invention furthermore provides a reservoir which can be used in sucha device, comprising a layer of a material which can be impregnated witha solution of the active principle with a view to transdermal deliveryof this active principle to a patient, through a face of this layerwhich is applied against the skin of the patient, noteworthy in that itcomprises an electrode permeable to the solution of active principle,applied to the said face of the layer of the impregnatable material.

Other characteristics and advantages of the present invention willemerge on reading the following description and on examining theattached drawing, in which:

FIG. 1 is a diagrammatic representation of a reservoir according to thepresent invention, in exploded cross-section,

FIG. 2 is a diagrammatic representation of a device for implementing themethod according to the invention, already partially described in thepreamble of the present description, and

FIG. 3 is a plot used in the measurement method according to theinvention.

Reference is now made to FIG. 1 which shows that the reservoir 1according to the invention comprises, in addition to the layer 2 ofhydrogel impregnated with a solution of active principle in ionized formand the first electrode 7 which applies the therapeutic current, asecond electrode 10, for measurement, mounted for example on a frame 10'and placed on that face of the layer 2 which is opposite the face laidagainst the first electrode 7. Advantageously, the reservoir 1 comprisesanother layer 12 of neutral hydrogel deposited on the electrode 10 so asto come into contact with the skin of a patient during transdermaldelivery of medicinal products assisted by iontophoresis, for purposeswhich will be described below.

It will be noted, incidentally, that the first electrode 7 may, as avariant, be integral with the electronic module 4, the hydrogel layer 2of the reservoir being placed in contact with this electrode just beforedelivery of a medicinal product, for example.

According to the invention, the measurement electrode 10 is permeable tothe solution of active principle, so that this solution can wet the skinof the patient. Purely by way of example, this electrode may consist ofa fine wire grid, with a mesh spacing of 1 wire /2 mm or 0.5 wire/2 mm,for example.

Furthermore, the device represented in FIG. 2 comprises means 11supplied by the potential difference picked up between the electrodes 7and 10 during passage of the therapeutic current established by thegenerator 5, these means 11 delivering to the microcontroller a voltagesignal V which is an image of the said potential difference. This signalis subjected in the microcontroller 6 to an analog/digital conversionwith a view to subsequent calculations. The means 11 constitute amatching stage, which matching can be carried out conventionally using adifferential amplifier, for example.

As seen hereinabove, the microcontroller 6 controls the amplitude, thewave form, etc. of the current delivered by the generator 5. Thus, themicrocontroller knows exactly, the instant when it picks up the voltageV, the current I which passes through the electrode 7 and the layer ofhydrogel impregnated with active principle.

From these two parameters, it is possible to deduce the overallconductivity of the layer (2) of hydrogel, which conductivity is afunction of the quantity of ions of the active principle which arepresent in the layer 2 at the moment of the measurement of I and V. Ifthe only ions present in the layer of hydrogel are those of the activeprinciple, the quantity of active principle present in the layer can bededuced from the measurement of the conductivity of the layer alone.

In fact, however, the layer of hydrogen often contains other ionizedspecies. This is, in particular, true when, as is conventional, theactive principle is introduced into the layer of hydrogel by means of asaline solution of sodium chloride, for example. If the active principleis present in the solution in the form of positively charged ions, it isclear that the co-ions Na⁺ of the solution influence, as a function oftheir concentration and their mobility, the overall conductivity of thelayer 2. Similarly, if the electrode 7 is made of silver/silverchloride, Ag⁺ ions may be found in the layer 2, which affect itsconductivity.

In practice, according to the invention, account is taken of all theions which may affect the conductivity of the layer 2, other than thoseof the active principle, by carrying out prior calibration operationsbased on measurements carried out in vitro and/or in vivo, theseoperations making it possible to establish the plot illustrated by FIG.3, which makes it possible to derive the quantity of active principlecontained in the layer 2 just by measuring the voltage V between theelectrodes 7 and 10.

The basis for construction of this plot may be an "in vitro" measurementcell comprising a chamber for a medium holding the ions of an activeprinciple which have passed through a skin sample attached to thereservoir in FIG. 2, under iontophoretic assistance. The concentrationof active principle in the holding medium is then periodicallydetermined and the voltage V then observed between the electrodes 7 and10 is picked up (graph A). By subtraction, graph B, illustrating thedecrease in the quantity Q of active principle remaining in thereservoir, as a function of time, is derived from the concentrationmeasurements.

This plot, once set up, is used as follows: during transdermal deliveryof a given active principle in a given solution of given startingconcentration, a voltage V₁ between the electrodes 7 and 10 is measuredat some instant. This voltage makes it possible to determine, on thegraph A, a point A₁ of ordinate V₁, and then a point B₁ on the graph B,having the abscissa of A₁. The ordinate Q₁ of B₁ gives the quantity ofactive principle contained at the instant of the measurement in thereservoir according to the invention.

Measurements of concentration in the plasma, carried out in vivo on apatient under treatment by known means, for example chromatographical orelectrochemical, might also make it possible to establish the plot inFIG. 3.

According to another advantageous characteristic of the device accordingto the invention, the microcontroller 6 comprises memory means (notshown) loaded with a table, derived from the plot in FIG. 3, forming acorrespondence between a set of values of the voltage V and a set ofvalues of the quantity Q of active principle contained in the reservoir.By virtue of knowledge of this quantity Q at any instant, themicrocontroller constructs a feedback signal which can be used incontrol of the therapeutic current by the microcontroller 6, in order tocompel the strength of this current to follow a predetermined timeprogram, corresponding to a predetermined program for medicinal productdelivery.

It will be noted that the control of this current thus established makesit possible to take account of variations in the iontophoreticefficiency, from one patient to another, and variations over time of thepermeability to the active principle of the skin of a patient.

Of course, the invention is not limited to the embodiment described andrepresented, which was given only by way of example. Thus, in the periodof measuring the quantity of active principle which is passed into theblood of the patient, use may be made of a current having a strengthwhich is different from that of the therapeutic current. The measurementcan then be carried out in a current/voltage range which is chosen so asto shield the measurement from possible physiologically inducedinterference.

Similarly, the reservoir may comprise a measurement electrode 10 havinga form other than that of a metal grid, for example that of an openworked film plated with a metal layer, or else an open worked film madeof an electrically conducting polymer material.

The layer of hydrogel 12 which covers the external face of themeasurement electrode 10 has several functions. First, it is used forensuring adhesion of the measurement electrode onto the skin of apatient whilst reducing the irritation of the skin. It is also used forisolating the electrode 10 from ions such as K⁺, Na⁺, Cl⁻ normallypresent on the skin of the patient owing to perspiration. It is alsoused for protecting the measurement electrode when the reservoir is notapplied to the skin of a patient.

The hydratable polymer or hydrogel constituting the layer 2 may bereplaced by other materials such as a felt, a sponge or any othermaterial capable of absorbing a liquid.

It is also clear that the invention extends to determination of thequantity of active principle in ionized form which is passed into theblood of a patient by transdermal delivery even though this deliverymight not be assisted by iontophoresis. However, it is particularly wellsuited to an iontophoretic device by virtue of the presence therein ofthe essential part of the electrical and electronic means necessary.

We claim:
 1. Method for measuring the quantity of an active principlecontained in an ionized form in a reservoir comprising of a layer of amaterial impregnated with a solution of said active principle, whereinthe conductivity of the impregnated material is measured and ameasurement of the quantity of active principle contained in thereservoir is derived from said conductivity measurement.
 2. Methodaccording to claim 1, wherein, in order to measure the conductivity ofthe impregnated material, a current of predetermined strength is passedthrough the latter, and the electric voltage which then appears betweentwo electrodes separated by at least a part of the layer of theimpregnated material is measured.
 3. Method according to claim 2,wherein the quantity of active principle contained in the reservoir isderived from a plot established during a prior calibration phase andgiving said quantity as a function of said measured voltage.
 4. Methodaccording to claim 3, wherein the said plot is established on the basisof measurements of quantities of active principle which have passedthrough a skin sample under transdermal delivery of the active principleassisted by iontophoresis, carried out in an in vitro measurement cell.5. Method according to claim 3, wherein the said plot is established onthe basis of measurements of quantities of active principle which havepassed through the skin of a patient.
 6. Device for implementing themethod according to claim 1, comprising a) first and second electrodesplaced on either side of and in electrical contact with at least a partof the layer of the impregnated material of the reservoir, b) means forpassing the electric current of predetermined strength through theimpregnated material and c) means sensitive to the voltage picked upbetween said electrodes in order to calculate the quantity of activeprinciple contained in said reservoir.
 7. Device according to claim 6,wherein said calculation means are incorporated in an electronic modulefor generating and controlling a therapeutic electric current fortransdermal delivery of the active principle, assisted by iontophoresis.8. Device according to claim 7, wherein said means for passing theelectric current through the impregnated material comprise a generatordelivering a current passing between said first electrode and saidsecond electrode, the latter being in electrical contact with the skinof a patient.
 9. Device according to claim 6, wherein the calculationmeans comprise memory means loaded with a table giving the quantity ofactive principle contained in the reservoir as a function of theelectric voltage measured between the electrodes, the table constitutingan image of a plot established during a prior calibration phase andgiving said quantity as a function of said measured voltage.
 10. Deviceaccording to claim 9, comprising means for regulating a therapeuticcurrent on the basis of the measured quantity of active principle, so asto servo the quantity of active principle delivered to a patient to apredetermined time program.
 11. Reservoir for implementing the methodaccording to claim 1, comprising a layer of material impregnated with asolution of the active principle for transdermal delivery of said activeprinciple to a patient through a surface of said layer which is appliedagainst the skin of the patient, and a measurement electrode permeableto the solution of active principle, applied to said surface of thelayer of impregnated material.
 12. Reservoir according to claim 11,wherein said measurement electrode is in the form of a conductive grid.13. Reservoir according to claim 12, wherein the measurement electrodeis covered, on the side which is not in contact with the layer of theimpregnated material, with a layer of a neutral hydrogel.
 14. Reservoiraccording to claim 11, wherein the reservoir further comprises anelectrode, arranged in electrical contact with a surface of the layer ofimpregnated material which is opposite the surface in contact with themeasurement electrode.